Vitamin D in combination cancer treatment J o u

Journal of Cancer 2010, 1
http://www.jcancer.org
101
J
Jo ou ur rn na al l o of f C Ca an nc ce er r
2010; 1:101-107
© Ivyspring International Publisher. All rights reserved
Review
Vitamin D in combination cancer treatment
Yingyu Ma
1
, Donald L. Trump
2
and Candace S. Johnson
1 
1. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
2. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
 Corresponding author: candace.johnson@roswellpark. o r g
Published: 2010.07.15
Abstract
As a steroid hormone that regulates mineral homeostasis and bone metabolism, 1α,
25-dihydroxycholecalciferol (calcitriol) also has broad spectrum anti-tumor activities as
supported by numerous epidemiological and experimental studies. Calcitriol potentiates the
anti-tumor activities of multiple chemotherapeutics agents including DNA-damaging agents
cisplatin, carboplatin and doxorubicin; antimetabolites 5-fluorouracil, cytarabine, hydroxyu-
rea, cytarabine and gemcitabine; and microtubule-disturbing agents paclitaxel and docetaxel.
Calcitriol elicits anti-tumor effects mainly through the induction of cancer cell apoptosis, cell
cycle arrest, differentiation, angiogenesis and the inhibition of cell invasiveness by a num b e r o f
mechanisms. Calcitriol enhances the cytotoxic effects of gamma irradiation and certain an-
tioxidants and naturally derived compounds. Inhibition of calcitriol metabolism by
24-hydroxylase promotes growth inhibition effect of calcitriol. Calcitriol has been used in a
number of clinical trials and it is important to note that sufficient dose and exposure to cal-
citriol is critical to achieve anti-tumor effect. Several trials have demonstrated that safe and
feasible to administer high doses of calcitriol through intermittent regimen. Further well de-
s i g n e d c l i n i c a l t r i a l s s h o u l d b e c o n d u c t e d t o b e t t e r u n d e r s t a n d t h e r o l e o f c a l c i t r i o l i n c a n c e r
therapy.
Key words: vitamin D, calcitriol, cancer, chemotherapy
Introduction
Vitamin D is a steroid hormone that regulates
calcium homeostasis, bone metabolism and a variety
of other physiological functions (1). Vitamin D can be
obtained from ultraviolet light-induced photobioge-
nesis in the skin or from the diet (1). In the skin,
7-dehydrocholesterol is converted to vitamin D
3
,
which is hydroxylated to 25(OH)D
3
by
25-hydroxylase in the liver and then to 1,25(OH)
2
D
3
(1α, 25-dihydroxycholecalciferol, calcitriol), the hor-
monally active metabolite, by 1α-hydroxylase in the
kidney (1). Calcitriol is mainly catabolized by
24-hydroxylase (CYP24A1) to 1α,24,25(OH)
2
D
3
which loses its bioactivity (1).
Calcitriol acts through both genomic and
non-genomic mechanisms (2). In genomic pathways,
calcitriol binds to intracellular vitamin D receptor
(VDR), which subsequently heterodimerizes with
another nuclear receptor retinoid X receptor (RXR).
The heterodimer binds to vitamin D response element
in target genes and leads to gene transcription regu-
lation (1). In addition, calcitriol has rapid effects that
are independent of gene transcription regulation,
which are defined as non-genomic effects and not
mediated directly through steroid recep-
tor-l ig an d-DNA interaction. O n the other hand,
non-genomic actions may indirectly affect gene tran -
scription via the regulation of intracellular signaling
pathways that target transcription factors (3). Calci-
triol induces a number of non-genomic responses in-
cluding rapid intestinal absorption of calcium, release

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102
of calcium from intracellular stores, opening of vol-
tage-ga ted cal ci um and chloride channels, and the
activation of protein kinase C, protein kinase A,
phosphatidylinositol-3 kinase (PI3K) and phospholi-
p a s e C (4).
Vitamin D compounds in cancer prevention
and treatment
Numerous epidemiological and preclinical stu-
dies support a role of vitamin D compounds in cancer
prevention and treatment in colorectal, breast, pros-
tate, ovarian, bladder, lung and skin cancers and leu-
kemia (1, 5, 6). Low levels of plasma 25(OH)D
3
are
associated with higher cancer incidence and mortality
in men in colorectal, breast, lung and prostate cancers
(7-10). The broad spectrum anti-tumor effects of cal-
citriol and analogs are mostly based on inhibition of
cancer cell proliferation and invasiveness, induction
of differentiation and apoptosis, and promotion of
angiogenesis.
Calcitriol has been studied in various combina-
tion treatments and shown synergistic or additive
antitumor activities. Cisplatin (cis-diammine-
dichloro-platinum (II), cDDP) and its analog carbop -
latin (Di-amminecyclobutanedicarboxylatoplatinum,
CBDCA) are widely used DNA-damaging agents. It is
active in the treatment of testicular, ovarian, cervical,
lung, bladder cancer and head and neck squamous
cell carcinoma (SCC) (11, 12). Calcitriol enhances both
carboplatin and cisplatin-mediated growth inhibition
in breast cancer MCF-7 cells and prostate cancer
LNCaP and DU145 cells (13, 14). Calcitriol potentiat e s
cisplatin anti-tumor effect in a Y-79 human retinob-
lastoma xenograft model (15) and canine breast can -
cer, osteosarcoma, and mastocytoma cells (16).
Ro23-7553 (1,25(OH)
2
-16-ene-23-yne-D
3
), a calcitriol
analog, inhibits tumor regrowth when combined with
cisplatin in a SCC model system (17). Calcitriol pro-
motes the expression of mitogen-activated protein
kinase kinase kinase (MEKK-1) and the cleavage of
caspase 3 when used in combination with cisplatin in
SCC cells (18). Additional studies support these find-
ings. SCC-VII and a calcitriol-resistant variant SCC
(SCC-DR), generated by continuous culturing of SCC
cells in calcitriol-containing media and has
non-inducible VDR, are resistant to cisplatin (19).
Pretreatment with calcitriol sensitizes SCC cells to
cisplatin-induced growth inhibition and results in
enhanced clonogenic cell kill in SCC. This effect is not
seen in SCC-DR cells in vitro and in vivo. This sensi-
tization may be due to restored apoptotic pathway, as
indicated by enhanced cleavage of pro-caspase 10 and
PARP and increased DNA fragmentation. Calcitriol
and cisplatin suppress SCC tumor growth much bet-
ter than either agent alone (19). Further study shows
that calcitriol increased the protein level of p73, a p53
family member, which contributed to calcitriol and
cisplatin-mediated growth inhibition in SCC cells (19).
Calcitriol sensitizes breast cancer cells to another
DNA-damaging agent doxorubicin through the inhi-
bition of the expression and activity of cytoplasmic
antioxidant enzyme Cu/Zn superoxide dismutase,
which subsequently increases the oxidative damage
by doxorubicin (20). Tamoxifen and calcitriol or its
analog EB1089, KH1060, CB966 or OCT used together
lead to enhanced growth inhibition in breast cancer
cells MCF-7 than either agent alone (21). OCT and
tamoxifen also inhibit MCF-7 xenograft tumor pro-
gression (22).
Calcitriol also additively or synergistically po-
tentiates the anti-tumor activity of other types of
chemotherapeutic agents. Calcitriol promotes tumor
cell sensitivity to several antimetabolites, which in-
terfere with the synthesis of RNA and DNA. Calcitriol
enhances cellular sensitivity of human colon cancer
cells to 5-fluorouracil through calcium-sensing re-
ceptor (23). When added together or immediately
after ara-C (cytarabine), calcitriol promotes the ac-
cumulation of DNA fragments and cytotoxicity (24).
Calcitriol and cytarabine combination has been used
in clinic as the minimally intensive chemotherapy,
and prolonged remission in elderly patients with
acute myeloid leukemia (AML) and myelodysplastic
syndrome (MDS) (25, 26). Adenosine deami-
nase-resistant analog fludarabine synergistically en-
hances calcitriol-induced differentiation of human
monoblastic leukemia U937 cells (27). Hydroxyurea,
cytarabine or camptothecin acts synergistically with
calcitriol to inhibit human monoblastic leukemia U937
cell growth (28). Hydroxyurea also promotes calci-
triol-mediated U937 cell differentiation (28). Gemci-
tabine is a widely used antimetabolite, and the com-
bination of gemcitabine and cisplatin is the curre nt
standard chemotherapy regimen for locally advanced
and metastatic bladder cancer (29, 30). Calcitriol en-
hances caspase-dependent apoptosis and synergisti-
cally promotes the anti-proliferative effects of gemci-
tabine and cisplatin in human bladder cancer model
systems T24 and UMUC3 (31). We have shown in
vitro in SCC cells that p73 is important in calcitriol
antiproliferative effect; we are also examining p73
status in vivo in human transitional cell carcinoma.
The expression of p73 protein is lower in human
bladder cancer tissue compared with adjacent normal
tissue in 3 out of 4 pairs as assessed by immunoblot
analysis (31). Calcitriol augments p73 protein level in
T24 and UMUC3 bladder cancer cells, which may
contribute to this growth inhibition (31). Pretreatment

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with calcitriol in combination with gemcitabine and
cisplatin markedly inhibits T24 tumor growth in nude
mice (31). Anti-tumor activity of gemcitabine is also
augmented by calcitriol in Capan-1 human pancreatic
cancer model system, as suggested by enhanced
growth inhibition, apoptosis, inhibition of Akt sur-
vival pathway and xenograft tumor growth (32).
Calcitriol potentiates antitumor activity of mi-
crotubule-disrupting agents such as paclitaxel (33, 34)
and docetaxel (35). This effect is associated with re-
duced expression level of p21 in prostate cancer cell
PC3 (33) or increased Bcl-2 phosphorylation in breast
cancer cells (34), and multidrug resistance-associated
protein 1 (35), respectively. Calcitriol analog
1,25(OH)
2
-16-ene-23-yne-19-nor-26,27-F6-D
3
( LH) or
EB1089 also potentiates antitumor activity of pacli-
taxel in breast cancer model systems (36). Calcitriol
analog ILX 23-7553 additively enhances the antitumor
effects of both adriamycin and ionizing irradiation in
breast tumor cells MCF-7 through growth inhibition
and apoptosis induction (37). These substantial data
suggest that the addition of calcitriol to multiple
chemotherapy regimens increases the activity of such
treatments and potentially a better response rate to
the regimens.
VDR f o r m s h e t e r o d i m e r i n a s s o c i a t i o n w i t h R X R .
RXR ligand 9-cis-retinoic acid (9-ci s-RA) combined
with calcitriol results in delayed tumor progression in
the prostate PC3 tumor xenograft model in nude mice
(38). This combination treatment results in direct
binding of VDR/RXR heterodimer to the promoter
region of human telomerase reverse transcriptase
(hTERT) which inhibits the expression of hTERT and
subsequently leads to decreased telomerase activity in
prostate cancer cells (38). Calcitriol analog
20-epi-22oxa-24a,26a,27a-tri-homo-1α,25(OH)
2
D
3
(KH1060) synergizes with 9-cis-RA to inhibit the
growth and promote the differentiation of acute
promyelocytic leukemia cells NB4 (39) and myelob -
lastic cells HL-60 (40). The combination leads to in-
creased apoptosis which is accompanied by reduced
Bcl-2 expression and increased Bax expression (39).
The antitumor activity of calcitriol may also in-
volve histone deacetylation. Combining histone dea-
cetylase inhibitor sodium butyrate or trichostatin A
with calcitriol or its analog LH or
1α,25-( O H )
2
-16,23E-diene-26,27-hexafluoride-D
3
(LT)
synergistically suppresses calcitriol or analog-in du c ed
growth inhibition in prostate cancer cell lines LNCaP,
PC3 and DU145 (41). This effect is mediated by en-
hanced apoptosis instead of induction of cell cycle
arrest (41).
Besides chemotherapy, vitamin D is also used in
combination with other types of cancer treatment.
Calcitriol or its less calcaemic analogue
19-nor-1α,25-(OH)
2
D
2
acts synergistically with iro-
nizing radiation t o i n h i b i t t h e g r o w t h a n d a p o p t o s i s o f
LNCaP prostate cancer cells and primary tumor cells
(42). EB1089 potentiates the antitumor activity of iro-
nizing radiation partially through increased apoptosis
in breast cancer model system MCF-7 (43). Breast
cancer cells overexpress one of the NF-κB subunits
RelB, which promotes cancer cell survival. Calcitriol
treatment results in reduced mRNA and protein le-
vels of RelB and its target genes survivin, Bcl-2 a nd
MnSOD, and sensitizes the breast cancer cells Hs578T
and NF639 to gamma-irradiation. Overexpression of
RelB enhances NF639 cells survival following calci-
triol and irradiation treatment (44). Calcitriol pre-
treatment for 24 h enhances the phototoxic response
of human SCC A431 cells to methyl aminolaevuli-
nate-based photodynamic therapy (45).
Non-specific cyclooxygenase (COX) inhibitors
acetyl salicylic acid or indomethacin in combination
with calcitriol markedly induce differentiation of
leukemia cell lines into monocytes and cell cycle ar-
rest at G1 phase (46). Cell differentiation is dependent
on phosphorylation of Raf1 (46). The combination of
ibuprofen, a non-steroidal anti-inflammatory drug
(NSAID), and calcitriol results in greater growth in-
hibition and G1 cell cycle arrest in human prostate
cancer LNCaP cells compared to either agent alone
(47). A calcitriol analog 22-ox a-1α,25-(OH)
2
D
3
, when
used together with vitamin K
2
, promotes leukemia
cells HL-60 differentiate into monocytes as examined
by morphology and cell surface CD14 expression in a
synergistic nature (48). This combination also induces
cell cycle arrest at G0/G1 phase; however, it sup-
presses apoptosis compared to vitamin K
2
alone (48).
Carnosic acid, a plant-derived polyphenolic antioxi-
dant, enhances the monocytic differentiation effects of
calcitriol in human myeloid leukemia cells HL60 (49).
Decreased intracellular reactive oxygen species, in-
creased intracellular glutathione, and activ a t io n o f
Raf-1/MEK1/ERK1/2 pathway are observed with the
combination treatment (49). B r y o s t a t i n -1, a marine
bryozoan-derived natural compound, has antitumor
activities in both solid and lymphoid tumors (50).
B r y o s t a t i n -1 synergizes with calcitriol to induce mo-
nocytic differentiation of NB4 cells (50, 51), which is
associated with G1 phase cell cycle arrest, decreased
cell growth and increased plastic adhesion (50).
25(OH)D
3
, when used together with iron deprivation
agents including iron chelators or transferrin receptor
antibody A24, induces the differentiation of myeloid
leukemia cell lines and primary myeloblasts from
AML patients into monocytes/macrophages (52).
These effects are dependent on the increased level of

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reactive oxygen species and the activation of JNK
MAPK pathway (52).
Interaction of calcitriol with certain agents re-
sults in enhanced calcitriol anti-tumor activity. Ad-
ministration of dexamethasone (Dex), which reduces
calcitriol-induced hypercalcemia, prior to calcitriol
inhibits SCC cell proliferation compared to calcitriol
alone (53). Combined treatment with Dex and calci-
triol reduces SCC xenograft tumor growth. These
findings are associated with the observations that Dex
enhances VDR expression in SCC cells and VDR li-
gand binding activities in tumor cell extracts and
kidneys but decreases that in intestinal mucosa (53).
F u r t h e r s t u d i e s s h o w t h a t t h e c o m b i n a t i o n o f c a l c i t r i o l
and Dex apoptosis and cell cycle arrest at G0/G1 in
SCC cells (54). This combination also suppresses the
activation of Akt and ERK1/2 pathways (54).
The effect of calcitriol is modulated by its meta-
bolizing enzymes. The primary vitamin D
3
inactivat-
ing enzyme CYP24A1, a mitochondrial cytochrome
P450, induces calcitriol degradation and thereby inhi-
bits calcitriol biological activity. The broad spectrum
cytochrome P450 inhibitor ketoconazole (KTZ) or a
specific CYP24A1 inhibitor RC2204, which effectively
inhibits the expression and enzyme activity of
CYP24A1 in PC3 cells and mice kidney tissue, syner-
gistically inhibits the anti-proliferative effect of calci-
triol in human prostate PC3 cells (55). Dex is admi-
nistered together with KTZ to minimize calci-
triol-mediated hypercalcemia. Enhanced apoptosis is
observed which does not involve caspase 3 activation
but the translocation of apoptosis inducing factor
(AIF) to the nucleus. Calcitriol and ketoconazle/Dex
combination enhances the growth inhibition observed
with calcitriol alone in PC3 xenograft tumor mouse
model (55). KTZ also potentiates the anti-proliferative
effect of calcitriol or its analog EB1089 in prostate
cancer cells (56). An imidazole derivative liarozole
inhibits CYP24 activity in prostate cancer cells DU145
and thus sensitizes these cells to calcitriol-mediated
growth inhibition, which is associated with increased
VDR expression (57).
RRR-alpha-vitamin E succinate (VES), one of the
most effective vitamin E forms, induces VDR expres-
sion in prostate cancer cells (58). Pretreatment with
VES synergistically enhances calcitriol-mediated
growth inhibition of prostate cancer cells in vitro and
reduces the rate of prostate cancer xenograft tumor
growth (58), which allows for a low-dose calcitriol to
be administered. A glutathione-depleting compound,
menadione, sensitizes breast cancer cells MCF-7 t o
calcitriol-mediated growth inhibition, which may be
caused, at least in part, by the increased oxidative
stress, as shown by enhanced ROS production (59).
Genistein, an isoflavone found in soybeans and a
number of plants, in combination with calcitriol, in-
hibits cell growth in human prostate LNCaP cells,
which is dependent on increased expression of p21
and associated with increased VDR expression (60).
Another study shows that genistein and calcitriol
further reduce prostate DU145 cell proliferation
compared to either agent alone (61). The mechanisms
for this effect may involve the induction of mRNA
expression and enzyme activity of CYP24 by genistein
which leads to prolonged half-life of calcitriol (61).
Increased expression of VDR protein, VDR transcrip-
t i o n a l a c t i v i t y , a n d t h e e x p r e s s i o n o f V D R t a r g e t g e n e s
are also observed in the combination treatment group
(61). A medicinal herb ginseng (Panax ginseng C.A.
Meyer, Araliaceae) promotes calcitriol-in du c ed t h e
differentiation of leukemia cells HL-60 into mono-
cytes as assessed by expression levels of CD14 and
CD11b (62). This effect may be mediated by the
ERK1/2 and PKC, but not PI3K pathway (62).
Phosphorylated prolactin (PRL) antagonizes the
proliferation promoting effect of unmodified PRL.
Molecular mimicry of naturally phosphorylated hu-
man PRL at the major phosphorylation site S179,
S179D (PRL), sensitizes relatively vitamin
D-insensitive prostate cancer cells DU-145 and PC3 to
calcitriol-mediated anti-proliferative effect and
apoptosis, which is associated with increased VDR
and p21 expression (63). Secreted protein acidic and
rich in cysteine (SPARC; osteonectin, BM-40), a family
member of matricellular proteins including throm-
bospondins, tenascin, and osteopontin, may serve as a
tumor suppressor (64). Compared with parental
MIP101 colorectal cancer cells, calcitriol markedly
reduces cell growth and enhances calcitriol alone- o r
calcitriol+fluorouracil-induced apoptosis in
SPARC-overexpressing MIP101 cells (64). Calcitriol
treatment also suppresses the phosphorylation of Akt
and the expression of Bcl-2 family member BAD (64).
Calcitriol has been utilized in a number of clini-
cal studies, either alone or in combination with Dex or
cytotoxic agents, which has been reviewed (65, 66). It
is important to emphasize that anti-tumor activity of
calcitriol is dependent on its dose and exposure ac-
cording to preclinical studies. Exposure to high con-
centrations of calcitriol is necessary to achieve an -
ti-tumor results. Calcitriol or its analog Ro23-7553
delays SCC xenograft tumor growth in a dose de-
pendent manner (67). Calcitriol of 2.5 µg/mouse ad-
ministered twice a week results in a markedly
stronger tumor suppression compared with once a
week regimen in human pancreatic cancer model
system Capan-1 (32). Ph ar ma cokinectic (PK) studies
indicate that calcitriol of 0.125 µg/mouse results in a

Journal of Cancer 2010, 1
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105
C
max
> 1 0 . 0 n g / m l a n d A U C > 4 0 . 0 n g h / m L i n n o r m a l
mice (68), which exceeds the concentration needed for
calcitriol anti-tumor activity in vitro.
Although multiple clinical studies have been
conducted with calci t r i o l o r i t s a n a l o g s , t h e a n t i -tumor
results are largely disappointing. This may be due to
the fact that calcitriol or its analogs has been used at
much lower doses than maximum tolerated dose
(MTD) with the concern of dose-limiting hypercalce-
mia (69, 70). We and others demonstrate that suffi-
cient doses of calcitriol to achieve exposure similar to
those seen in preclinical models can be safely admi-
nistered by high dose intermittent regimen (once
weekly or QDx3 weekly) (69, 71-73). A recent phase I
clinical trial demonstrates that the MTD of calcitriol
(i.v.) is 74 µg/week when administered with gefitinib
(70). The C
max
of calcitriol at the MTD is 6.68 ± 1.42
ng/ml (16 ± 3.40 nmol/L), which is much higher than
the dose needed to elicit anti-tumor effect in preclini-
cal studies (70). The area under the curve (AUC) of
calcitriol at the MTD is 35.65 ± 8.01 ng h/mL (70). In
comparison, 75 µg of DN101, a weekly oral formula-
tion of calcitriol, results in a lower C
max
(3.8 nmol/L)
but similar AUC (38.4 ng h/mL) (74). These results
show that high doses of calcitriol can be administered
alone or in combination with other agents to elicit or
enhance the anti-tumor effects.
Summary
In summary, calcitriol has shown potential in
enhancing the antitumor activities of a variety of cy-
totoxic or differentiating agents. The combination
treatment studies with calcitriol do provide evidence
and support for the continued study of calcitriol in
cancer chemotherapies.
Conflict of Interest
The authors have declared that no conflict of in -
terest exists.
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